1. Field of the Invention
This invention relates to a stent which is implanted in a stenotic or occluded lesion of a body duct such as blood vessel, bile duct, trachea, esophagus, or urethra in order to maintain the opening of the lesion. More specifically, this invention relates to a stent which is capable of maintaining the opening of the lesion for a prolonged period by sustained release of a biologically/physiologically active substance from the stent surface, namely, by the gradual and slow release of such substance which has the effect of suppressing the restenosis.
2. Description of the Related Art
Angioplasty which is conducted in the case of ischemic heart disease is described as one typical example.
With the westernization of dietary habits in our country, the number of patients suffering from ischemic heart diseases (angina pectoris, cardiac infarction) has sharply increased. In order to treat the heart diseases, percutaneous transluminal coronary angioplasty (PTCA) has been developed and the number of cases where PTCA is applied has dramatically increased. Today, technological development has enabled application of the PTCA in a variety of cases, and the PTCA is applied not only to the cases where PTCA was originally applied namely, not only to the circumscribed lesion (with short lesion length) or the single vessel lesion (with the stenosis only at one vessel) but also to the cases wherein the lesion is located at a more distal site, eccentric, and calcined, or to the cases of multivessel lesion (with the stenosis at two or more vessels). PTCA is a procedure wherein a small incision is made in the artery in the thigh or arm of the patient to leave the introducer sheath in the incision; a guidewire is first introduced through the lumen of the introducer sheath; a hollow tube called a guide catheter is inserted in the blood vessel and over the guidewire to place the guide catheter at the entrance of the coronary artery; the guidewire is withdrawn; another guidewire and a balloon catheter is inserted in the lumen of the guide catheter and the balloon catheter is advanced through the coronary artery of the patient after the guidewire and under the X-ray radiography to the lesion, namely to the stenotic or occluded lesion of the blood vessel to place the balloon catheter at the lesion; and the balloon is inflated at this lesion at the predetermined pressure for 30 to 60 seconds for once or for several times by the physician. By this procedure, the inner cavity of the blood vessel at the site of the lesion is opened, and this opening is maintained. As a consequence, amount of blood flowing through the blood vessel becomes increased. However, intimal thickening occurs as the wound healing of the vascular wall in the case, for example, when wounds are made in the vascular wall by the catheter, and restenosis is reported in 30 to 40% of the PTCA cases.
There is no established method for preventing the restenosis. However, use of the stent, atherectomy catheter, and other device has been investigated, and these methods are starting to gain some results. The term xe2x80x9cstentxe2x80x9d used herein designates a hollow medical device which is implanted in the stenotic or occluded lesion of a blood vessel or other body duct to open the lesion and to maintain the opening for treating various diseases caused by such stenosis or occlusion of the body duct. A stent is a medical device which usually comprises a metal material or a polymer material, and various stents have been proposed. Exemplary such stents include those wherein small slots are formed on the side wall of the hollow tubular body of metal or polymer material, and those produced by braiding a metal wire or a polymer fiber into a cylindrical shape. A stent is implanted for the purpose of preventing or reducing the risk of the restenosis that may take place after the PTCA and other procedures. However, it has so far been unsuccessful to significantly prevent the restenosis by using the stent alone.
Recently, various attempts for reducing the occurrence of the restenosis have been made by loading the stent with various biologically/physiologically active substances such as a carcinostatic for local and sustainedly releasing the biologically/physiologically active substance at the lesion where the stent has been implanted. For example, JP 8-33718 A proposes a stent wherein a mixture of a therapeutical substance (biologically/physiologically active substance) and a polymer is coated on the surface of the stent main body, and JP 9-99056 A proposes a stent wherein a bioactive material layer (biologically/physiologically active substance layer) is formed on the surface of the stent main body, and a polymeric porous material layer is formed on the surface of the bioactive material layer.
However, in the case of the stent proposed in JP 8-33718 A, the therapeutic substance (biologically/physiologically active substance) is incorporated in the polymer, so that the stent is associated with the problem of decomposition and degradation of the biologically/physiologically active substance due to the chemical action with the polymer, that is, with the problem of the stability of the biologically/physiologically active substance. For example, when the polymer selected is polylactic acid, this polymer has the characteristic feature that it generates an acid upon its decomposition despite its favorable unique function that it is decomposable in the body and enables the release of the biologically/physiologically active substance. When an acid-sensitive substance is selected for the biologically/physiologically active substance, the decomposition of the polylactic acid will create the problem of the decomposition and degradation of the biologically/physiologically active substance. In addition, when the polymer selected has a high decomposition speed in the body, release of the biologically/physiologically active substance will be completed in a short period (within several days after the implantation) and the stent will suffer from the problem of insufficient suppression of the restenosis of the vascular wall. As a consequence, the stent of the type proposed in JP 8-33718 A is associated with the problem of limited combination of the polymer and the biologically/physiologically active substance used in the stent in view of preventing the decomposition and degradation of the biologically/physiologically active substance, and at the same time, in view of securing a reliable release of the biologically/physiologically active substance for a prolonged period (for several weeks to several months after the stent implantation).
On the other hand, in the case of the stent proposed in JP 9-99056 A, the bioactive material layer (biologically/physiologically active substance layer) and the polymer layer are formed as different layers, so that this stent is free from the risk of the decomposition and degradation of the biologically active substance by the action with the polymer. In this stent, however, the polymer layer covering the biologically/physiologically active substance comprises a porous material wherein passages are defined from one surface to the other surface of the polymer layer, and the biologically/physiologically active substance layer is exposed to the outer atmosphere of the stent (atmosphere outside the polymer layer) from the time of its production. Therefore, the stent of such structure is associated with the risk that the biologically/physiologically active substance is released through the passages present in the porous material before implanting the stent in the body. The stent of this type is also associated with the risk after implanting the stent in the lesion, namely, with the risk of the phenomenon that the biologically/physiologically active substance is rapidly released in a short period (within several days after the implantation), that is, the initial burst, and this stent suffered from the difficulty of sustained release of the biologically/physiologically active substance, namely, slow, gradual release of the biologically/physiologically active substance for a prolonged period (for several weeks to several months after the implantation).
In view of the situation as described above, an object of the present invention is to provide a stent wherein the biologically/physiologically active substance can be stably loaded on the stent main body without undergoing decomposition or degradation, and at the same time, wherein sustained release of the biologically/physiologically active substance, namely, slow, gradual release of the biologically/physiologically active substance for a prolonged period with no rapid release of the biologically/physiologically active substance is enabled once the stent is implanted in the lesion.
Such objects are attained by the present invention as described in the following (1) to (9).
(1) A stent to be implanted in a body duct comprising
a cylindrical stent main body extending in axial direction and having an opening on each end of the axially extending stent main body and
a sustained release coating formed on the surface of the stent main body from which a biologically/physiologically active substance is released; wherein
said sustained release coating comprises
a layer of the biologically/physiologically active substance formed on the surface of said stent main body, and
a polymer layer formed on said biologically/physiologically active substance layer to cover said biologically/physiologically active substance layer; and
said biologically/physiologically active substance layer comprises at least one biologically/physiologically active substance;
said polymer layer comprises a vapor or water-permeable polymer, and a water-swellable substance dispersed in said polymer and swollen by absorption of the vapor or the water; and
cracks are formed in said polymer layer when said water-swellable substance is swollen by absorbing the vapor or the water, and the biologically/physiologically active substance in said biologically/physiologically active substance layer is released to the exterior of said sustained release coating through said polymer layer.
(2) A stent according to the above (1) wherein said stent main body comprises a metal material.
(3) A stent according to the above (1) wherein said stent main body comprises a polymer material.
(4) A stent according to any one of the above (1) to (3) wherein said biologically/physiologically active substance layer comprises solely from the biologically/physiologically active substance.
(5) A stent according to any one of the above (1) to (3) wherein said biologically/physiologically active substance layer comprises the biologically/physiologically active substance and an additional component which imparts tackiness to said biologically/physiologically active substance layer.
(6) A stent according to any one of the above (1) to (5) wherein said biologically/physiologically active substance is at least one member selected from a carcinostatic, an immunosuppressive, an antibiotic, an antirheumatic, an antithrombotic, an antihyperlipidemic, an ACE inhibitor, a calcium antagonist, an integrin inhibitor, an antiallergic, an antioxidant, a GPIIb/IIIa antagonist, retinoid, flavonoid, carotenoid, a lipid improving agent, a DNA synthesis inhibitor, a tyrosine kinase inhibitor, an antiplatelet, a vascular smooth muscle antiproliferative agent, an antiinflammatory agent, a biological material, an interferon, and a NO production accelerator.
(7) A stent according to any one of the above (1) to (6) wherein said vapor or water-permeable polymer constituting the polymer layer is a member selected from silicone polymer, cellulose polymer, polyurethane, polyester, vinyl polymer, acrylic polymer, and thermoplastic elastomer.
(8) A stent according to any one of the above (1) to (7) wherein said water-swellable substance is a low molecular weight salt having a molecular weight of up to 1000.
(9) A stent according to the above (8) wherein said low molecular weight salt is a salt which is found in a body.
(10) A stent according to the above (8) or (9) wherein said low molecular weight salt is sodium chloride.